Although the penicillins and cephalosporins are widely used in medicine, there is continued interest in obtaining new, synthetic .beta.-lactam antibiotics to combat strains of microorganisms that acquire resistance to .beta.-lactam antibiotics currently in use.
A recently developed approach to the total synthesis of .beta.-lactam antibiotics employs as its key step, the reaction of an .alpha.-azidoacyl chloride and an imino compound in the presence of a tertiary amine to form the .alpha.-azido-.beta.-lactam nucleus. Several 6-epipenicillin, penam and cepham derivatives have been synthesized from the .alpha.-azido-.beta.-lactam intermediate. Reduction of the azido group after .beta.-lactam formation and modification of the .alpha.-amino-.beta.-lactam nucleus will provide the desired antibiotic.
Isocephalosporins, which have sulfur positioned at the 2 position of the 6 membered ring instead of the 1 position as in cephalosporins, and 0-2-isocephalosporins which are the oxa analogs have also been synthesized via the .alpha.-azido-.beta.-lactam technique. ##STR1## Though not occurring in nature, the isocephalosporins synthesized are reported to have antibiotic activity comparable to that of cephalosporins. [D. B. Bryan et al., J.Am.Chem.Soc., 1977, 99 2352; T. W. Doyle et al., Can. J. Chem., 1977 55, 2873; for a review of the chemistry of the .alpha.-azido-.beta.-lactam approach, see B. G. Christensen et al., Ann. Rev. Med. Chem., Chapt. 28, 271 (1976)].
Commercial preparation of any of the .beta.-lactam antibiotics by the .alpha.-azido-.beta.-lactam route requires large scale procesing and bulk quantities of reagent ingredients. Unfortunately such quantities and scales create serious drawbacks for the method. For example, the required reagents such as azidoacetic acid and azidoacetyl chloride have been reported to be prone to violent decomposition, especially during such large scale purification techniques as distillation. The reduction of an .alpha.-azido-.beta.-lactam to .alpha.-amino-.beta.-lactam also requires careful control to ensure a high yield of the desired product. Otherwise, .beta.-lactam cleavage may occur during the reduction and subsequent acylation of the .alpha.-azido-.beta.-lactam, [Bose et al., J. Or. Chem., 1973, 38, 1238].
Therefore, development of an alternative synthetic method that is not hazardous and gives high yields without the necessity of precisely controlled conditions is desirable.
Furthermore, the known methods of the preparation of isocephalosporins and analogs involve non-chiral starting material. To obtain biologically active, chiral final products from these known methods, optical resolution of the final product or an intermediate close to the final product is necessary, [See, for example, Conway et al., Cana. J. Chem., 1978, 56, 1335]. Such optical resolution usually leads to the waste of about 50 percent of the .beta.-lactam antibiotic or a close intermediate. Therefore, development of an alternate synthetic method that provides optically active final products without a resolution step is desirable.